Genetic epidemiology of hematopoietic cell transplant outcomes

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Allogeneic hematopoietic cell transplant (allo-HCT) is a time of high metabolic demand. There are immediate needs for restoration of blood formation and response to fever and infection, as well as ongoing challenges of graft versus host disease (GVHD) and possibly graft versus leukemia effects. HCT outcomes have significantly improved with matching refinement of the nuclear DNA human leukocyte antigen (HLA) system, which contains genes encoding for the major histocompatibility complex. However, there were no studies to our knowledge that considered whether mitochondrial DNA and/or mitochondrial DNA matching affected HCT outcomes. Mitochondria (mt) provide cells energy through oxidative phosphorylation (OXPHOS), regulate cell survival and death, and are increasingly thought to functionally influence innate and adaptive immune system responses. Polymorphisms in mtDNA can be grouped into haplotypes (mthaps) that are associated with human global migration. MtDNA contains no introns and therefore polymorphisms can have a direct effect on coding sequences. In support, cybrid (cell clones that have identical nuclear DNA but different mtDNA) studies show evidence of OXPHOS and other functional differences (including immune response) among various mthaps. Numerous association studies have linked specific mthaps to disease occurrence, severity and/or therapy response. We explored whether patient or donor mthaps (H, J, U, T, Z, K, V, X, I, W, K2) were associated with allo-HCT outcomes in 437 patients and 327 donors. We found that certain donor and recipient mthaps (e.g., K, K2, V, W, J, U) may be determinants of mortality, GVHD and/or relapse in HCT recipients. Here, we will validate our initial findings in a much larger, homogenous patient population to further investigate the role of mthaps in allo-HCT. We will obtain DNA and comprehensive clinical data from the National Marrow Donor Program on over 4200 unrelated donors and 4200 HCT recipients and perform NextGen sequencing of the mt genome to establish mthaps. We also will build upon our recent in vivo studies of mt function and explore the functional significance of mthaps in HCT. Our specific aims are to 1) Determine whether recipient or donor mthaps are associated with HCT outcomes; and 2) Investigate whether mismatch between donor and recipient mthaps in HCT is associated with adverse outcomes. A secondary aim is to explore whether mthap phenotypes associated with extreme HCT clinical outcomes (e.g., K2, V) compared to H vary with regard to percent human stem cell engraftment in immunodeficient (NOD-SCID IL2rγnull ("NSG")) mice. Our study will provide necessary validation of our initial results, investigate the role of mismatching of mthaps in HCT outcomes, and provide in vivo and in vitro data of the functional significance of mthaps in the context of HCT. If our preliminary results are confirmed, they could ultimately lead to worldwide implementation of additional selection criteria to identify optimal allo-HCT donors to reduce risk of adverse HCT outcomes.